We have identified a truncated SR-family protein that has potent antiviral activity against HIV-1, HIV-2, and SIV, but no activity against MLV. Ectopic expression of the truncated SR-protein in human or mouse cells restricts the nuclear entry of HIV pre-integration complexes. Selection of HIV resistant to this factor leads to mutation in the virus capsid protein. Notably, these HIV mutants lose the ability to infect nondividing cells, and one mutation in particular interferes with HIV infection of terminally differentiated macrophages. We believe this to be a significant advance. In the era of molecular HIV studies, the discrete elements within HIV that are required for the infection of nondividing cells has proven to be a vexing question despite the sustained interest of gene therapists and HIV researchers. We are currently seeking cellular proteins targeted by the antiviral factor to better understand the machinery HIV interacts with in the infection of nondividing cells. We are also studying how the capsid mutations alter the biology of early HIV replication.Theoretically similar studies have been initiated using libraries of molecules to block cellular protein synthesis via RNA interference (RNAi). Cells that restrict HIV infection and express unique RNAi molecules have been identified. The nature of the virus replication block and the role of the cellular genes thought to be targeted by the RNAi molecules in HIV infection is currently being examined.